Role of glycans in cholesteryl ester transfer protein revealed by molecular dynamics simulation
Role of glycans in cholesteryl ester transfer protein revealed by molecular dynamics simulation
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分子动力学模拟揭示聚糖在胆固醇酯转移蛋白中的作用
DOI：
10.1002/prot.25520
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发表时间：
2018-08-01
影响因子：
2.9
通讯作者：
Zhang, Shengli
中科院分区：
文献类型：
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作者：
Hao, Dongxiao;Yang, Zhiwei;Zhang, Shengli
目前的胆固醇酯转移蛋白（CETP）抑制剂是基于非糖基化的晶体结构设计的，并且它们中的大多数未能治愈心血管疾病（CVD）。对我们来说，研究CETP的糖基化结构（CETP - G）以及聚糖对CETP结构和功能的影响尤为重要。在此，我们使用了总计3.0秒的CETP新生结构（CETP - N）和CETP - G的分子动力学（MD）轨迹来研究它们的结构差异，以便为CETP介导的脂质交换提供新的见解。根据我们的模拟和先前的突变研究，相对于CETP - N，CETP - G呈现出更伸展的形状，其N端的疏水和亲水可及溶剂表面积（SASA）更高且振幅更大，其中聚糖88通过N端为胆固醇酯（CEs）提供部分辅助作用。聚糖341降低了颈部翻盖的灵活性，干扰了胆固醇酯通过颈部区域的转运。此外，聚糖240降低了螺旋 - X的灵活性以干扰胆固醇酯的转移。聚糖396降低了C端的灵活性并增加了其疏水可及溶剂表面积。总体而言，这些聚糖通过与周围残基形成氢键影响CETP的动力学和结构，并且聚糖的采样构象也受其周围残基的影响。因此，聚糖是CETP不可或缺的一部分，对CETP抑制和心血管疾病治疗的进一步研究应充分考虑聚糖的影响。
Current cholesteryl ester transfer protein (CETP) inhibitors are designed based on the unglycosylated crystal structure, and most of them have failed to cure cardiovascular disease (CVD). It is particularly important for us to investigate the glycosylation structure of CETP (CETP‐G) and effect of glycans on the structure and function of CETP. Here, we used a total of 3.0‐μs molecular dynamics (MD) trajectories of nascent structure of CETP (CETP‐N) and CETP‐G to study their structural differentiations, to shed new light on the CETP‐mediated lipid exchange. In accordance with our simulations and previous mutation studies, relative to CETP‐N, CETP‐G adopts a more stretched shape with higher hydrophobic and hydrophilic solvent‐accessible surface area (SASA) of N‐terminal oscillating with larger amplitude, in which Glycan88 provides partial assistance for CEs through the N‐terminal. Glycan341 reduces the flexibility of neck flap, with the interference of CEs through the neck region. Besides, Glycan240 reduces the flexibility of Helix‐X to interfere the CEs transfer. Glycan396 decreases the flexibility and increases the hydrophobic SASA of C‐terminal. Overall, these glycans affect the dynamics and structure of CETP through forming H‐bonds with surrounding residues, and the sampled conformations of glycan is also affected by its surrounding residues. Thus, glycans are an integral part of CETP, further studies on the CETP inhibition and treatment of CVD should fully consider the effect of glycans.